Antidepressant azaheterocyclylmethyl derivatives of 1,4-dioxino[2,3-b]pyridine

ABSTRACT

Compounds of the formula                  
 
useful for the treatment of depression, obsessive compulsive disorder, panic attacks, generalized anxiety disorder, social anxiety disorder, sexual dysfunction, eating disorders, obesity, addictive disorders caused by ethanol or cocaine abuse, and dysthymia.

This application is a continuation of application Ser. No. 10/127,923,filed Apr. 23, 2002, now U.S. Pat. No. 6,656,950, which claims thebenefit of Application Ser. No. 60/286,301, filed Apr. 25, 2001, thedisclosures of which are both incorporated herein by reference in theirentireties.

BACKGROUND OF THE INVENTION

Major depression is a serious health problem affecting more than 5% ofthe population, with a life-time prevalence of 15–20%.

Selective serotonin reuptake inhibitors have produced significantsuccess in treating depression and related illnesses and have becomeamong the most prescribed drugs. They nonetheless have a slow onset ofaction, often taking several weeks to produce their full therapeuticeffect. Furthermore, they are effective in fewer than two-thirds ofpatients.

Serotonin selective reuptake inhibitors (SSRIs) are well known for thetreatment of depression and other conditions. SSRIs work by blocking theneuronal reuptake of serotonin, thereby increasing the concentration ofserotonin in the synaptic space, and thus increasing the activation ofpostsynaptic serotonin receptors.

However, although a single dose of an SSRI can inhibit the neuronalserotonin transporter which would be expected to increase synapticserotonin, long-term treatment is required before clinical improvementis achieved.

It has been suggested that the SSRIs increase the serotonin levels inthe vicinity of the serotonergic cell bodies and that the excessserotonin activates somatodendritic autoreceptors, 5HT_(1A) receptors,causing a decrease in serotonin release in major forebrain areas. Thisnegative feedback limits the increment of synaptic serotonin that can beinduced by antidepressants.

A 5HT_(1A) antagonist would limit the negative feedback and shouldimprove the efficacy of the serotonin reuptake mechanism. (Perez, V., etal., The Lancet, 349:1594–1597 (1997)). Such a combination therapy wouldbe expected to speed up the effect of the serotonin reuptake inhibitor.

Thus, it is highly desirable to provide improved compounds which bothinhibit serotonin reuptake and which are antagonists of the 5HT_(1A)receptor.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelcompounds of the formula:

wherein

-   -   R¹ is selected from hydrogen, hydroxy, halo, cyano, carboxamido,        carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl        of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,        alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or        di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,        alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to        6 carbon atoms;    -   R², R³, R⁴ and R⁶ are independently selected from hydrogen,        halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms,        alkoxy of 1 to 6 carbon atoms, and alkanoyloxy of 2 to 6 carbon        atoms; and    -   R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms;    -   X is CR⁶ or N;    -   A dotted line represents an optional double bond;    -   (O) represents optional oxidation; and    -   n is an integer 0, 1 or 2;        or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present invention R¹ is hydrogen,hydroxy, halo, cyano, trifluoromethyl, amino, mono- or di-alkylamino inwhich each alkyl group has 1 to 6 carbon atoms, alkyl of one to sixcarbon atoms or alkoxy of one to six carbon atoms. In still morepreferred embodiments R¹ is hydrogen.

In other preferred embodiments of the invention R², R³ and R⁴ areindependently selected from hydrogen, halo, cyano, alkyl of one to sixcarbon atoms, or alkoxy of one to six carbon atoms. In still morepreferred embodiments of the invention R², R³ and R⁴ are independentlyselected from hydrogen, cyano or halogen.

In still other preferred embodiments of the invention R³ is hydrogen orlower alkyl.

X is preferably CR⁶. When X is CR⁶, then R⁶ is preferably hydrogen,halo, cyano, alkyl of one to six carbon atoms or alkoxy of one to sixcarbon atoms, and more preferably hydrogen, cyano or halogen.

Of the compounds of Formula I, the preferred members are those in whichR¹ is attached to the 6-position of the 1,4-dioxino[2,3-b]pyridine andis hydrogen, hydroxy, halo, cyano, trifluoromethyl, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkylof one to six carbon atoms or alkoxy of one to six carbon atoms; R², R³and R⁴ are independently selected from hydrogen, halo, cyano, alkyl ofone to six carbon atoms, or alkoxy of one to six carbon atoms; n is aninteger 0 or 1; and R⁵, X, (O) and the dotted line are defined as above.

Most preferred are those examples in which R¹ is hydrogen, hydroxy oralkoxy of one to six carbon atoms, R², R³ and R⁴ are independentlyselected from hydrogen, halo and cyano, R⁵ is hydrogen, X is CR⁶, R⁶ ishydrogen, halo, or cyano, n is 0, (O) is defined as above and the dottedline represents a double bond.

This invention relates to both the R and S stereoisomers of the3-amino-methyl-1,4-dioxino[2,3-b]pyridines, as well as to mixtures ofthe R and S stereoisomers. Throughout this application, the name of theproduct of this invention, where the absolute configuration of the3-aminomethyl-1,4-dioxino[2,3-b]pyridines is not indicated, is intendedto embrace the individual R and S enantiomers as well as mixtures of thetwo. In some embodiments of the present invention the S stereoisomer ispreferred.

Where a stereoisomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. Substantially free asused herein means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,N.Y., 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

Furthermore, it is appreciated that, when R¹ is attached to the6-position of the 1,4-dioxino[2,3-b]pyridine and is hydroxy, themolecule may exist as either the pyridone or pyridinol tautomer. Theclaims in this application or intended to embrace both tautomers, aswell as mixtures of the two.,

Alkyl as used herein refers to an aliphatic hydrocarbon chain andincludes straight and branched chains such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1to 3 carbon atoms.

Alkanamido as used herein refers to the group R—C(═O)—NH— where R is analkyl group of 1 to 5 carbon atoms.

Alkanoyloxy as used herein refers to the group R—C(═O)—O— where R is analkyl group of 1 to 5 carbon atoms.

Alkanesulfonamido as used herein refers to the group R—S(O)₂—NH— where Ris an alkyl group of 1 to 6 carbon atoms.

Alkoxy as used herein refers to the group R—O— where R is an alkyl groupof 1 to 6 carbon atoms.

Carboxamido as used herein refers to the group —CO—NH₂.

Carboalkoxy as used herein refers to the group R—O—C(═O)— where R is analkyl group of 1 to 5 carbon atoms.

Halogen (or halo) as used herein refers to chlorine, bromine, fluorineand iodine.

Pharmaceutically acceptable salts are those derived from such organicand inorganic acids as: acetic, lactic, citric, cinnamic, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids.

Specific compounds of the present invention include:

3-{[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro-[1,4]-dioxino[2,3-b]pyridine;

3-{[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro-{1,4]dioxino[2,3-b]pyridine;

3-{1-[2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole-5-carbonitrile;and

3-{[4(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine;and pharmaceutical salts thereof.

The compounds of the invention are most conveniently prepared by themethod outlined in Scheme I below. Unless otherwise noted, the variablesare as defined above. Specifically, the appropriately substituted2-bromo-3-pyridinol (1) is alkylated with glycidyl tosylate ornitrobenzenesulfonate or an epihalohydrin in the presence of a suitablebase such as sodium hydride or potassium carbonate. The resultingglycidyl ether (2) is heated with the appropriate azaheterocycle in ahigh

boiling solvent such as dimethyl sulfoxide to effect an opening of theepoxide to a vicinal amino alcohol (3). Cyclization of the secondaryalcohol to the title compounds of the invention is accomplished bytreatment with catalytic palladium acetate and2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl [Tol-BINAP] in thepresence of sodium or potassium carbonate.

Alternatively, the appropriately substituted 2-bromo-3-pyridinol (1) maybe alkylated either with an epihalohydrin or glycidyl tosylate asdescribed above or with α,β-isopropylidene-γ-tosylate as shown in SchemeII below and then treated with dilute aqueous acid to give the vicinaldiol (4). The primary alcohol is selectively protected with a suitableprotecting group such as a t-butyl dimethylsilyl (TBS) ether to produce(5) and then cyclization to th pyridodioxan effected by treatment withcatalytic palladium acetate and Tol-BINAP in the presence of potassiumcarbonate as described above to produce (6). Following deprotection ofthe pyridodioxan alcohol

via treatment with tetra-n-butylammonium fluoride (TBAF) in methanol andconversion to the tosylate with p-toluenesulfonyl chloride (TsCl) in thepresence of a tertiary base and catalytic dimethylaminopyridine (DMAP)to produce (7), the title compounds of the invention are produced byreaction with the appropriate azaheterocycle in a high boiling solventsuch as dimethylsulfoxide. Oxidation of the pyridodioxan-3-methyltosylate or silyl ether with meta-chloroperoxybenzoic acid (m-CPBA) orhydrogen peroxide leads to the compounds of the invention which arepyridine-N-oxides.

The pyridine-N-oxide also allows convenient access to the compounds ofthe invention which are substituted in the 6-position as shown in SchemeIII below. Treatment of the N-oxide (8) with phosphorus oxyhalide givesthe 6-halo derivative (9), which can be treated with a primary orsecondary amine to give the 6-mono- or dialkylamino derivatives (13), orwith sodium cyanide to give the 6-nitrile. Treatment of the N-oxide withacetic anhydride, followed by hydrolysis with mild base, gives the6-hydroxy derivative (11). Treatment of the N-oxide withp-toluenesulfonyl chloride followed by the appropriate alcohol gives the6-alkoxy derivative (12). Treatment of the N-oxide with trimethysilylazide and reduction with hydrogen over palladium on carbon yields the6-amino derivative (10). Replacement of the tosylate with theappropriately substituted azaheterocycle as described above gives thetitle compounds of the invention.

The azaheterocycles appropriate to the invention are known compounds orthey can be prepared by one schooled in the art. The compounds of theinvention may be resolved into their enantiomers by conventional methodsor, preferably, they may be prepared directly by substitution of(2R)-(−)-glycidyl tosylate or (R)-α,β-isopropylidene-γ-tosylate (for theR pyridodioxan-3-methylamine) or (2S)-(+)-glycidyl tosylate or(S)-α,β-isopropylidene-γ-tosylate (for the S enantiomer) in place ofepichlorohydrin in the procedures above.

Like the antidepressants fluoxetine, paroxetine and sertraline, thecompounds of this invention have the ability to potently block thereuptake of the brain neurotransmitter serotonin. They are thus usefulfor the treatment of depression and other diseases commonly treated bythe administration of serotonin selective reuptake inhibitor (SSRI)antidepressants, such as obsessive compulsive disorder, panic attacks,generalized anxiety disorder, social anxiety disorder, sexualdysfunction, eating disorders, obesity, addictive disorders caused byethanol or cocaine abuse and related illnesses. Moreover, the compoundsof this invention have potent affinity for and antagonist activity atbrain 5-HT_(1A) serotonin receptors. Recent clinical trials employingdrug mixtures (eg, fluoxetine and pindolol) have demonstrated a morerapid onset of antidepressant efficacy for a treatment combining SSRIactivity and 5-HT_(1A) antagonism (Blier and Bergeron, 1995; F. Artigaset. al., 1996; M. B. Tome et. al., 1997). The compounds of the inventionare thus exceedingly interesting and useful for treating depressiveillnesses.

A protocol similar to that used by Cheetham et. al. (Neuropharmacol.32:737, 1993) was used to determine the affinity of the compounds of theinvention for the serotonin transporter. The compound's ability todisplace ³H-paroxetine from male rat frontal cortical membranes wasdetermined using a Tom Tech filtration device to separate bound fromfree ³H-paroxetne and a Wallac 1205 Beta Plate® counter to quantitatebound radioactivity. K_(i)'s thus determined for standard clinicalantidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and67.6 nM for zimelidine. A strong correlation has been found between³H-paroxetine binding in rat frontal cortex and ³H-serotonin uptakeinhibition.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OHDPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al., J. Neurochem. 44, 1685(1985) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)'s.

Antagonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol. 109: 1120, 1993), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OHOPAT. The testcompound's maximum inhibitory effect is represented as the I_(max),while its potency is defined by the IC₅₀.

The results of the three standard experimental test procedures describedin the preceding three paragraphs were as follows:

5-HT Transporter Affinity 5-HT_(1A) Receptor Affinity 5-HT_(1A) FunctionCompound KI (nM) KI (nM) IC₅₀ (nM) (I_(max)) Example 1 9.50 14.30 197.0(62.0) Example 2 2.39 6.81  57.0 (94.0) Example 3 2.58 22.40   183(100%) Example 4 1.21 10.16 618.0 (77.0)

Hence, the compounds of this invention are combined serotonin reuptakeinhibitors/5-HT_(1A) antagonists and are useful for the treatment ofdiseases commonly treated by the administration of serotonin selectivereuptake inhibitor (SSRI) anti-depressants, such as depression(including but not limited to major depressive disorder, childhooddepression and dysthymia), anxiety, panic disorder, post-traumaticstress disorder, premenstrual dysphoric disorder (also known aspre-menstrual syndrome), attention deficit disorder (with and withouthyperactivity), obsessive compulsive disorder (includingtrichotillomania), social anxiety disorder, generalized anxietydisorder, obesity, eating disorders such as anorexia nervosa, bulimianervosa, vasomotor flushing, cocaine and alcohol addiction, sexualdysfunction (including premature ejaculation), and related illnesses.

Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remingtons Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The amount provided to a patent will vary depending upon what is beingadministered, the purpose of the administration, such as prophylaxis ortherapy, and the state of the patient, the manner of administration, andthe like. In therapeutic applications, compounds of the presentinvention are provided to a patient already suffering from a disease inan amount sufficient to cure or at least partially ameliorate thesymptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age and responsepattern of the patient. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the human.

Provide as used herein means either directly administering a compound orcomposition of the present invention, or administering a prodrug,derivative or analog which will form an equivalent amount of the activecompound or substance within the body.

The present invention includes prodrugs of compounds of Formula I.“Prodrug”, as used herein means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of Formula I.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113–191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews,8:1–38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); and Higuchi and Stella (eds.) Prodriugs as Novel Drug DeliverySystems, American Chemical Society (1975).

The following examples illustrate the production of representativecompounds of this invention.

INTERMEDIATE 1 2-Bromo-3-[oxiranylmethoxy]pyridine

To a mixture of 25.2 g (0.145 mole) of 2-bromo-3-pyridinol and 30 g(0.22 mole) of potassium carbonate in 80 mL of N,N-dimethylformamide wasadded 30 g (0.13 mole) of (S)-glycidyl tosylate. The mixture was heatedunder nitrogen at 55–60° C. for 15 hours. The solvent was then removedin vacuum and replaced with 500 mL of methylene chloride, and thesolution was washed with 500 mL of water and with saturated brine, driedover sodium sulfate, filtered and concentrated in vacuum. The residuewas column chromatographed on silica gel with methylene chloride aseluant to give 17 g of the (S)-enantiomer of the title compound as awhite solid. ¹H-NMR (CDCl₃): multiplet 8.01 δ (1H); multiplet 7.22 δ(2H); doublet of doublets 4.38 δ (1H); multiplet 4.04 δ (1H); multiplet3.40 δ (1H); multiplet 2.95 δ (1H); multiplet 2.85 δ (1H).

EXAMPLE 13-{[4-(1H-indol-3-yl)-3,6-dihydr-1(2H)-pyridinyil]methyl}-2,3-dihydro[1,4dioxino[2,3-b]pyridine

3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole (1.03 g, 5.22 mmole) and2-bromo-3-[(2S)-oxiranylmethoxy]pyridine (0.80 g, 3.47 mmole) werecombined in DMSO (25 mL). This solution was heated at 75–80° C. undernitrogen for 5 hours. After completion, the reaction was cooled to roomtemperature and partitioned between 250 mL each of ethyl acetate andsaturated sodium bicarbonate. The organic phase was washed with brine,dried over magnesium sulfate and concentrated in vacuum. The cruderesidue was column chromatographed on silica gel using first methylenechloride as eluant to remove impurities and then 3% methanol inmethylene chloride to elute the product, which upon concentration invacuum, gave a yellow solid (1.05 g, 71%). 0.55 g (1.28 mmole) of thisyellow intermediate was then cyclized in toluene (50 mL) in the presenceof palladium (II) acetate (0.015 g, 0.061 mmole),(S)(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.052 g, 0.077mmole), and potassium carbonate (0.21 g, 1.5 mmol). The heterogeneousmixture was heated to 100° C. for a period of 24 hours. After themixture cooled to room temperature, the catalysts were removed byfiltration and the filtrate was concentrated to a crude brown oil, whichwas then column chromatographed on silica gel with 3% methanol inmethylene chloride as eluant to give the desired product as a brown oil(0.23 g, 52%). The oil was crystallized from ethanol with the additionof a solution of oxalic acid (0.04 g) in hot ethanol to give 0.10 g ofthe (S)-enantiomer of the title compound as a yellow solid oxalate, m.p.116° C.

Elemental Analysis for: C₂₁H₂₁N₃O₂.C₂H₂O₄.H₂O Calc'd: C, 60.65; H, 5.53;N, 9.23 Found: C, 60.94; H, 5.32; N, 8.89

EXAMPLE 23-{[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro{1,4]dioxino[2,3-b]pyridine

5-Fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.16 g, 5.37mmole) and 2-bromo-3-[(2S)-oxiranylmethoxy]pyridine (0.83 g, 3.6 mmole)were combined in DMSO (40 mL). This solution was heated at 75–80° C.under nitrogen for 5 hours. After completion, the reaction was cooled toroom temperature and partitioned between 250 mL each of ethyl acetateand saturated sodium bicarbonate. The organic phase was washed withbrine, dried over magnesium sulfate and concentrated in vacuum. Thecrude residue was column chromatographed on silica gel using firstmethylene chloride as eluant to remove impurities and then 3%MeOH/CH₂Cl₂ to elute the product, which was a yellow solid (0.90 g,56%). The intermediate (0.90 g, 2.01 mmole) was then cyclized in toluene(40 mL) in the presence of palladium (II) acetate (0.02 g, 0.09 mmole),(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.085 g, 0.12mmole), and potassium carbonate (0.33 g, 2.4 mmole). The heterogeneousmixture was heated to 100° C. for a period of 24 hours. After themixture cooled to room temperature, the catalysts were removed byfiltration and the filtrate was concentrated in vacuum. The resultingcrude brown oil was then column chromatographed on silica gel with 3%methanol in methylene chloride to give the desired product as a brownoil (0.23 g, 33%). The oil was crystallized from ethanol with theaddition of a solution of oxalic acid (0.05 g) in hot ethanol to give0.24 g of the (S)-enantiomer of the title compound as a white solidhemioxalate, m.p. 124° C.

Elemental Analysis for: C₂₁H₂₀FN₃O₂.0.50 C₂H₂O₄.H₂O Calc'd: C, 61.68; H,5.41; N, 9.80 Found: C, 61.96; H, 5.02; N, 9.80

EXAMPLE 33-{1-[2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole-5-carbonitrile

3-(1,2,3,6-Tetrahydro-4-pyridinyl)1H-indole-5-carbonitrile (1.62 g, 7.26mmole) and 2-bromo-3-[(2S)oxiranylmethoxy]pyridine (0.84 g, 3.65 mmol)were combined in DMSO (40 mL). This solution was heated at 75–80° C.under nitrogen for 5 hours. After completion, the reaction was cooled toroom temperature and partitioned between 250 mL each of ethyl acetateand saturated sodium bicarbonate. The organic phase was washed withbrine, dried over magnesium sulfate and concentrated in vacuum. Thecrude residue was column chromatographed on silica gel using firstmethylene chloride as eluant to remove impurities and then 3% methanolin methylene chloride to elute the product, which was a yellow foam(0.30 g, 18%). The intermediate (0.30 g, 0.66 mmole) was then cyclizedin toluene (40 mL) in the presence of palladium (II) acetat (0.015 g,0.067 mmole), (S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl(0.032 g, 0.047 mmole), and potassium carbonate (0.13 g, 0.94 mmole).The heterogeneous mixture was heated at 100° C. for a period of 30hours. After the mixture cooled to room temperature, the catalysts wereremoved by filtration and the filtrate was concentrated in vacuum. Theresulting crude brown oil was then column chromatographed on silica gelwith 3% methanol in methylene chloride to give the desired product as abrown oil (0.100 g, 42%). The oil was crystallized from ethanol with theaddition of a solution of oxalic acid in hot ethanol to give 0.050 g ofthe (S)-enantiomer of the title compound as a white solid, m.p. 165° C.

Elemental Analysis for: C₂₂H₂₀N₄O₂.1.4 C₂H₂O₄ Calc'd: C, 59.76; H, 5.61;N, 11.24 Found: C, 59.77; H, 4.95; N, 10.89

EXAMPLE 43-{[4-(6-Fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine

6-Fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.87 g, 8.65mmole) and 2-bromo-3-[(2S)oxiranylmethoxy]pyridine (1.00 g, 4.34 mmole)were combined in DMSO (45 mL). This solution was heated at 75–80° C.under nitrogen for 5 hours. After completion, the reaction was cooled toroom temperature and partitioned between 250 mL each of ethyl acetateand saturated sodium bicarbonate. The organic phase was washed withbrine, dried over magnesium sulfate and concentrated in vacuum. Thecrude oil was column chromatographed on silica gel using first methylenechloride as eluant to remove impurities and then 3% methanol inmethylene chloride to elute the product, which was a yellow solid (0.30g, 15%). The intermediate (0.30 g, 0.67 mmole) was then cyclized intoluene (40 mL) in the presence of palladium (II) acetate (0.010 g,0.044 mmole), (S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl(0.030 g, 0.044 mmole), and potassium carbonate (0.11 g, 0.80 mmole).The heterogeneous mixture was heated at 100° C. for a period of 24hours. After the mixture cooled to room temperature, the catalysts wereremoved by filtration and the filtrate was concentrated in vacuum. Theresulting crude brown oil was then column chromatographed on silica gelwith 3% methanol in methylene chloride to give the desired product as abrown oil (0.19 g, 79%). The oil was crystallized from ethanol with theaddition of a solution of oxalic acid in hot ethanol to give 0.070 g ofthe (S)-enantiomer of the title compound as beige solid dioxalate, m.p.120° C.

Elemental Analysis for: C₂₁H₂₀FN₃O₂.2C₂H₂O₄ Calc'd: C, 55.05; H, 4.43;N, 7.70 Found: C, 55.40; H, 4.42; N, 7.48.

1. A method of treating a subject suffering from a condition selectedfrom obesity, anorexia nervosa, bulimia nervosa, vasomotor flushing,alcohol addiction, and premature ejaculation, comprising the step of:providing to said subject suffering from said condition atherapeutically effective amount of a compound of formula I:

wherein R¹ is selected from hydrogen, hydroxy, halo, cyano, carboxamide,carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; R², R³, R⁴, and R⁶ are independently selected from hydrogen,halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, and alkanoyloxy of 2 to 6 carbon atoms; R⁵ ishydrogen or alkyl of 1 to 6 carbon atoms; X is CR⁶ or N; a dotted linerepresents an optional double bond; (O) represents optional oxidation;and n is an integer 0, 1, or 2; or a pharmaceutically acceptable saltthereof.
 2. A method according to claim 1, wherein said condition isanorexia nervosa or bulimia nervosa.
 3. A method according to claim 1,wherein said subject is a human.
 4. A method according to claim 1,wherein R¹ is hydrogen.
 5. A method according to claim 1, wherein R²,R³, and R⁴ are independently selected from hydrogen, halogen, and cyano.6. A method according to claim 1, wherein R⁵ is hydrogen or lower alkylof 1–3 carbon atoms.
 7. A method according to claim 1, wherein X is CR⁶.8. A method according to claim 1, wherein R⁶ is hydrogen, halo, orcyano.
 9. A method according to claim 1, wherein R¹ is attached to the6-position of the 1,4-dioxino[2,3-b]pyridine and is hydrogen, hydroxy,halo, cyano, trifluoromethyl, amino, mono- or di-alkylamino in whicheach alkyl group has 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atomsor alkoxy of 1 to 6 carbon atoms; R², R³, and R⁴ are independentlyselected from hydrogen, halo, cyano, alkyl of 1 to 6 carbon atoms, andalkoxy of 1 to 6 carbon atoms; n is the integer 0 or 1; or apharmaceutically acceptable salt thereof.
 10. A method according toclaim 9, wherein R⁶ is hydrogen, halo, or cyano.
 11. A method accordingto claim 1, wherein R¹ is attached to the 6-position of the1,4-dioxino[2,3-b]pyridine and is hydrogen, hydroxy or alkoxy of 1 to 6carbon atoms; R², R³, and R⁴ are independently selected from hydrogen,halo, and cyano; R⁵ is hydrogen; X is CR⁶; n is 0; and the dotted linerepresents a double bond; or a pharmaceutically acceptable salt thereof.12. A method according to claim 1, wherein said compound is3-{[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridineor a pharmaceutically acceptable salt thereof.
 13. A method according toclaim 1, wherein said compound is3-{[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridineor a pharmaceutically acceptable salt thereof.
 14. A method according toclaim 1, wherein said compound is3-{1-[2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole-5-carbonitrileor a pharmaceutically acceptable salt thereof.
 15. A method according toclaim 1, wherein said compound is3-{[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridineor a pharmaceutically acceptable salt thereof.